This proposal will examine the pathogenesis of neurologic involvement in Lyme disease. There are two specific aims: (1) immunologically define Neuroborreliosis syndromes due to direct spirochete invasion of the nervous system; (2) immunologically define syndromes due to indirect spirochete- triggered mechanisms. These aims will be approached through analysis of isolated immune complexes (IC), as well as cells and soluble factors, from the sequestered intrathecal cerebrospinal fluid (CSF) compartment. This approach is supported by preliminary data showing antigens and antibodies can be sequestered within IC, and hidden from detection. Findings will be statistically correlated with different syndromes. 1. Direct mechanisms a) the presence of free or IC-bound B. burgdorferi antigens will be determined, using monoclonal antibodies. b) the isotype, antigenic specificity, and relative proportions of free and IC-bound B. burgdorferi antibodies will be analyzed, using ELISA and immunoblot. 2. Indirect mechanisms a) infectious vs. immune specificity of complexes will be determined, using different IC assays, ELISA, and immunoblot. b) free and IC-bound autoantibodies to neural antigens will be characterized, using ELISA and immunoblot. c) cytokines and soluble immune activation markers (including CD4, CD8, Tac) will be measured, using ELISA and immunoblot. d) lymphocyte subsets and plasma cells will be defined, using monoclonal antibodies and immunocytochemistry. CSF and serum will be studied from patients with B. burgdorferi infection and otherwise unexplained neurologic involvement. Selected patients will be studied at single time points, pre and post therapy, nad serially. Controls will include other neurological disease patients, and patients with B. burgdorferi infection but no neurologic involvement. These studies will provide basic information on the central nervous system response to B. burgdorferi, will establish data on CSF abnormalities in American Neuroborreliosis, and will provide critical leads to the pathogenesis of various neurologic syndromes in Lyme disease.